cardiomiopatia periparto 2016

Contemporary Reviews in Cardiovascular Medicine
Peripartum Cardiomyopathy
Zolt Arany, MD, PhD; Uri Elkayam, MD
Abstract—Peripartum cardiomyopathy is a potentially life-threatening pregnancy-associated disease that typically arises in
the peripartum period and is marked by left ventricular dysfunction and heart failure. The disease is relatively uncommon,
but its incidence is rising. Women often recover cardiac function, but long-lasting morbidity and mortality are not infrequent.
Management of peripartum cardiomyopathy is largely limited to the same neurohormonal antagonists used in other forms
of cardiomyopathy, and no proven disease-specific therapies exist yet. Research in the past decade has suggested that
peripartum cardiomyopathy is caused by vascular dysfunction, triggered by late-gestational maternal hormones. Most
recently, information has also indicated that many cases of peripartum cardiomyopathy have genetic underpinnings. We
review here the known epidemiology, clinical presentation, and management of peripartum cardiomyopathy, as well
as the current knowledge of the pathophysiology of the disease. (Circulation. 2016;133:1397-1409. DOI: 10.1161/
CIRCULATIONAHA.115.020491.)
Key Words: cardiomyopathies ◼ heart failure ◼ pre-eclampsia ◼ pregnancy
H
eart failure associated with pregnancy and the peripartum period was recognized in the literature as early as
the 1800s by Virchow and others.1,2 The first large case series
was published in New Orleans in 1937,3,4 but the syndrome
remained poorly defined until the seminal publications by
Demakis and Rahimtoola5 and Demakis et al6 in 1971. Those
authors published data on 27 patients, specifically defined the
syndrome as occurring in the peripartum period, and first introduced the term peripartum cardiomyopathy (PPCM). The subsequent advent of echocardiography allowed the noninvasive
characterization of the syndrome, and the criterion of ejection fraction (EF) <45% was introduced in 1999 by a National
Heart, Lung, and Blood Institute workshop on PPCM.7,8
Despite these advances, PPCM is not a precisely defined
entity. The working group on PPCM of the European Society
of Cardiology recently provided an updated operational definition of PPCM as cardiomyopathy with reduced EF, usually <45%, presenting toward the end of pregnancy or in the
months after delivery in a woman without previously known
structural heart disease.9 The absence of preexisting heart disease is usually presumed rather than known because cardiac
imaging before clinical presentation is almost never available
in these young patients. The working definition also includes
entities such as Takotsubo cardiomyopathy, which is likely a
different disease process, sometimes distinguishable by echocardiographic criteria.10
The timing of PPCM is also not certain. Demakis et al6
originally noted that most cases occur in the first weeks after
delivery. Seventy-five of 123 patients with PPCM in a 2005
Southern California case series11 and 35 of 100 cases in a
2014 northern US series12 presented in the first week postpartum. This timing differs strikingly from the onset of the
major hemodynamic shifts of pregnancy, including reduced
afterload, increased blood volume, and up to 40% increase
in cardiac output, all of which occur early in the second trimester.13 However, PPCM also can present well before and
up to months after delivery. A study of 23 patients with idiopathic dilated cardiomyopathy (DCM) presenting before the
last month of pregnancy found them to be clinically indistinguishable from patients with classically defined PPCM.11 As
a consequence of these uncertainties, not all PPCM studies
define the disease equivalently, raising caution in comparisons
of results between studies.
The imprecise nature of the definition reflects our stillincomplete understanding of PPCM. The cause of the disease
remains unknown. Many potential causes have been proposed,
including viral myocarditis, nutritional deficiencies, autoimmunity, microchimerism, and hemodynamic stresses.14 Most
recently, experimental progress has strongly suggested a role
for vascular dysfunction, hormonal insults, and underlying
genetics. These new and developing data are discussed in
more detail below.
Epidemiology
The incidence of PPCM in the United States ranges from ≈1 in
1000 to 4000 live births (Figure 115–18). The range of incidence
likely reflects different population demographics, rigor of
definition, and underreporting resulting from a lack of awareness or misdiagnosis. A recent national inpatient database
analysis of 64 million discharge hospital records from 1000
hospitals in 47 states identified 34 219 cases of PPCM, with
an incidence of 1 in 968 births.18 More than half of the cases
of PPCM occurred in southern United States, likely reflecting racial differences (see below). The incidence is increasing,
From Perelman School of Medicine, University of Pennsylvania, Philadelphia (Z.A.); and Department of Medicine, Division of Cardiovascular Medicine
and Department of Obstetrics and Gynecology, University of Southern California, Los Angeles (U.E.).
Correspondence to Zolt Arany, University of Pennsylvania, SCTR 11-106, 3400 Civic Blvd, Philadelphia, PA 19104. E-mail [email protected]
© 2016 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.115.020491
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1397
1398 Circulation April 5, 2016
Figure 1. Recent multi-institutional estimates of
peripartum cardiomyopathy (PPCM) incidence
in the United States. Data taken from Mielniczuk
et al,15 Brar et al,16 Gunderson et al,17 and Kolte
et al.18
for example, in the above study from 8.5 to 11.8 per 10 000
live births between 2004 and 2011 and in a previous study
also of national hospital discharges from 2.3 to 4.5 per 10 000
live births between 1990 and 2002.15 The increasing incidence
may reflect increased awareness and diagnosis, rising maternal age, changing demographics, or rising multifetal pregnancies. As the apparent incidence of PPCM increases and
as treatments of other complications of pregnancy improve,
PPCM increasingly contributes to mortality. In a population
study of maternal cardiovascular deaths in California between
2002 and 2006, PPCM was the leading cause (23%).19
The incidence of PPCM outside the United States is less
well documented. Data in Africa and Asia suggest an incidence of ≈1 in 1000 live births.20–23 There are, however, striking “hot spots” of PPCM, the cause of which remains unclear.
In Haiti, the incidence of PPCM may be as much as 1 in 300
live births,24 possibly related to racial background, nutritional
deficiencies, or a high prevalence of preeclampsia. In northern
Nigeria, the incidence of PPCM has been reported as high as
1 in 100 live births,25 originally ascribed to indigenous customs of hot baths and high salt intake in the peripartum period,
although a recent case-control study of 39 PPCM cases does
not support this conclusion.26
Associated Conditions
Age
The incidence of PPCM is strongly associated with age. Even
though the disease can strike women of any age, >50% of
cases occur in women >30 years of age,15,16,18,27 with an odds
ratio of 10 in a comparison of women >40 and <20 years of
age.18
Race
The incidence of PPCM in the United States is notably higher
in blacks. More than 40% of cases in the nationwide studies described above occurred in black women,15,18 and half
occurred in the southern United States.18 A population study
in California noted an incidence of PPCM in blacks of 1 in
1421, nearly 3 times that in whites (1 in 4075).16 A singlecenter case-control study in Georgia and Tennessee found a
16-fold higher incidence of PPCM in black women compared
to white women.28 A case-control study of 52 black and 104
white patients with PPCM in Southern California showed
that black patients are typically younger, have a higher prevalence of hypertension, present later, and have a lower rate
of recovery of left ventricular (LV) EF.29 In a 2012 statewide
population study of cases in North Carolina in 2003, the incidence of PPCM in black women was 4 times that of white
women (1:1087 versus 1:4266), and the fatality rate at 5-year
follow-up was also 4 times as high (24% versus 6%).30 In
summary, PPCM strikes black women more often, and these
women fare worse (prognosis is described in more detail
below).
Preeclampsia and Hypertension
Preeclampsia and hypertension strongly predispose to PPCM.
A recent meta-analysis of 22 studies covering 979 cases of
PPCM showed an overall prevalence of preeclampsia of
22%, >4 times the 3% to 5% population prevalence.31 Any
hypertensive disorder (preeclampsia, gestational hypertension, or chronic hypertension) was present in 37% (range,
29%–45%) of cases. No clear geographic or racial differences
were detected. A recent study of hospital discharge records
in 6 states identified 535 patients with PPCM, of whom
29.3% had preeclampsia and 46.9% had hypertension (odds
ratio, 13.6 and 13.4, respectively).32 The prevalence of preeclampsia in many of these studies may be underestimated
because preeclampsia is often underreported and misclassified and because the presence of preeclampsia is often used
as an exclusion criterion from the diagnosis of PPCM. PPCM
is also frequently found in association with eclampsia, with
an odds ratio of 12.9 in a California population study of 1888
patients with eclampsia33 and 27.9 in the multistate hospital
discharge study of PPCM cases noted above.18
It is important to realize that preeclampsia or pregnancyinduced hypertension can also trigger pulmonary edema in
the absence of PPCM. A recent report directly compared 30
cases of PPCM with 53 cases of hypertension-associated heart
failure in pregnancy in a single referral center in South Africa
and found that hypertension-associated heart failure typically
presented before delivery, was associated with cardiac hypertrophy and preserved EF, and had a better prognosis.34 Even in
the absence of clinical heart failure, a number of echocardiographic studies have shown that preeclampsia causes diastolic
dysfunction, measured by various parameters, including E/E’,
myocardial performance index, and myocardial strain.35–37
The diastolic dysfunction is in part independent from blood
pressure elevations and can persist up to 1 year after delivery
and resolution of preeclampsia. Preeclampsia thus instigates
significant cardiac toxicity, which can be clinically silent but
can also present as pulmonary edema with preserved EF or as
part of PPCM. However, it is equally important to realize that
PPCM is not simply a manifestation of severe preeclampsia.
More than 90% of women with preeclampsia, even if severe,
do not develop PPCM, and conversely, at least 50% of women
with PPCM do not have preeclampsia. The 2 diseases are thus
different entities with a strong association and overlap. This
strong association suggests that PPCM and preeclampsia may
share pathophysiological mechanisms, as discussed in more
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Arany and Elkayam Peripartum Cardiomyopathy 1399
detail below. In short, suspicion for PPCM should not be lowered in the presence of preeclampsia. Doing so could delay
appropriate treatment.
Multiple Gestations
PPCM frequently presents in cases of multigestational status.
In the meta-analysis noted above, the average rate of twin gestations in cases of PPCM across 16 studies was 9%,31 well
above the average estimated prevalence of 3%.38 A number
of cases of PPCM with triplet pregnancies have also been
reported.39–41
Other associated conditions have been reported but less
well substantiated, including substance abuse, anemia,
asthma, prolonged tocolysis, diabetes mellitus, obesity, and
malnutrition.
Presentation and Diagnosis
The majority of PPCM cases present postpartum, mostly in
the week after delivery, whereas a small subset present during the second and third trimesters (Figure 2).6,11,13,42 Most
women present with signs and symptoms of heart failure,
including orthopnea and paroxysmal nocturnal dyspnea. These
symptoms can be confused with those of normal pregnancy,
especially of late gestation, a fact that often leads to missed
or delayed diagnosis of PPCM and to underestimation of the
incidence of this condition. Physical examination often reveals
signs of heart failure, including tachycardia, elevated jugular
venous pressure, pulmonary rales, and peripheral edema. Signs
of LV dilatation, including third heart sound and displaced apical impulse, are sometimes but not often noted because PPCM
can occur even without LV enlargement. ECG typically shows
sinus tachycardia with nonspecific changes, and chest radiography usually shows cardiac enlargement and pulmonary
venous congestion. Catastrophic presentations can occur,
with severe respiratory distress and low-output cardiac failure
necessitating pharmacological and mechanical support.43
The differential diagnosis includes pulmonary causes (eg,
pneumonia facilitated by the immune tolerance elicited during pregnancy or pulmonary embolism resulting from the
hypercoagulable peripartum period), acute pulmonary edema
from prolonged tocolysis or preeclampsia, and cardiac causes,
including myocardial infarction or Takotsubo cardiomyopathy. Echocardiography is generally sufficient to differentiate
from these causes and usually shows LV dilatation of variable
degrees, LV systolic dysfunction, right ventricular and biatrial
enlargement, mitral and tricuspid regurgitation, and pulmonary hypertension.8,41
Biomarkers
No specific diagnostic biomarkers for PPCM are currently
available. Levels of brain natriuretic peptide and troponin do
not normally rise during or after pregnancy and are typically
elevated in PPCM. Recent work (described in more detail
below) has suggested that microRNAs, specifically miR146a, may serve as a novel biomarker for PPCM compared
with unaffected postpartum women or women with idiopathic
DCM.44 More research is needed, however, including testing
to determine whether miR-146a levels differentiate PPCM
from peripartum myocardial infarction and other acute vascular events.
Treatment and Complications
There are limited data on treatment approaches to PPCM,
and only 2 randomized, controlled trials comprising a total of
44 patients have been reported (discussed further below).45–47
Treatment for PPCM is thus based largely on clinical experience and extrapolation from data with other forms of systolic heart failure. Treatment is focused, as with other forms
of systolic failure, on controlling volume status, neutralizing
maladaptive neurohormonal responses, and preventing thromboembolic and arrhythmic complications. Diuretic agents,
including loop diuretics, and nitrates are the agents of choice
for volume control, although caution is required if used before
delivery to avoid hypotension and impaired uterine perfusion. Neurohormonal blockade with angiotensin-converting
enzyme inhibitor inhibitors or angiotensin receptor blockers
can be used postpartum but is contraindicated before delivery, during which time a combination of organic nitrates
and hydralazine can be used instead. β-Blockade should be
considered and is likely safe during pregnancy. Metoprolol
tartrate may be favored in light of a more extensive clinical experience compared with other β-blockers. In addition,
Figure 2. Comparison of timing during and after pregnancy of hemodynamic changes, exemplified as cardiac output (CO; in black), elevations in prolactin and soluble Fms-like tyrosine kinase 1 (sFlt1) hormones (red), and incidence of peripartum cardiomyopathy (PPCM; blue
bars). Modified from Elkayam42 and Liu and Arany.13 *Prl levels stay elevated in women who nurse.
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β-1–selective agents may be preferable during pregnancy to
avoid promoting uterine activity. Digoxin can be safely used
during pregnancy, but its role in the treatment of systolic heart
failure is currently being debated.48,49
Studies of new experimental therapies have thus far been
equivocal or negative. A small 1999 nonrandomized study of 6
patients given intravenous immunoglobulin showed improvement compared with 11 historical control subjects,50 but no
further studies have been conducted. (A subsequent placebocontrolled, randomized trial of intravenous immunoglobulin
in 62 patients with recent-onset DCM, although none of them
with PPCM, did not show improvements with intravenous
immunoglobulin treatment.51) Another 2002 South African
study reported improved outcomes in 30 patients receiving
pentoxifylline compared with 29 historical control subjects,45
but again, no further studies have been conducted. A 2011 randomized, controlled trial of 24 women with PPCM comparing
levosimendan, a calcium sensitizer used in acutely decompensated heart failure, with placebo showed no differences in
clinical or echocardiographic outcomes.52
Bromocriptine and Cessation of Breastfeeding
Recent mechanistic research (discussed below) has implicated
the hormone prolactin in the origin of PPCM and suggested
that inhibition of pituitary prolactin secretion with cessation
of lactation or with bromocriptine, an ergot alkaloid and dopamine D2-receptor agonist, may be beneficial.53 Bromocriptine
is approved by the US Food and Drug Administration for
the treatment of Parkinson disease, galactorrhea, and certain
pituitary tumors. It has been shown to improve cardiovascular outcomes in diabetes mellitus54 and to have favorable
neurohormonal and hemodynamic effects in patients with
heart failure.55 A small 2010 randomized, open-label, singlecenter trial of bromocriptine in 20 African women with newly
diagnosed PPCM showed improvements in LV recovery at 6
months (27% versus 58%; P=0.012) and in combined heart
failure end points. In a prospective, observational registry in
Germany, the use of bromocriptine was twice as common in
women showing echocardiographic improvement (n=82) than
in those who did not (n=14; P=0.013).56 However, enthusiasm for these early results has been tempered by the small
size of the unblinded, randomized, controlled trial study, the
surprisingly frequent adverse outcomes in the control arm of
the study, and the potential danger of using bromocriptine in
the peripartum period. Bromocriptine was deemed in 1982
to be safe to the fetus,57 but its approval for the suppression
of lactation was withdrawn in the United States in 1995 as a
result of concerns about adverse maternal vascular events.58
Moreover, potential harm to the newborn by suppression of
lactation must be considered, in particular in the developing
world where undernutrition and unsafe water supplies account
for the majority of childhood mortality, rendering reliance on
breast milk critical.59 A retrospective Internet-recruited study
in the United States showed that breastfeeding was associated with a better, rather than worse, maternal outcome.60 In
summary, the use of bromocriptine and voluntary cessation
of lactation remain investigational and of uncertain benefit at
this time. We hope that the results of an ongoing prospective,
randomized, controlled trial of bromocriptine in 60 patients in
Germany61 will provide more information on the efficacy and
safety of bromocriptine.
Thromboembolism and Anticoagulation
PPCM is associated with higher rates of thromboembolism
than other forms of cardiomyopathy.42 The peripartum period
is a hypercoagulable state,62 likely an evolutionary adaptation
to minimize postpartum hemorrhaging (historically the most
common cause of maternal death). Cardiac dilation, endothelial injury, and immobility additionally contribute to clotting
propensity in PPCM. In the nationwide inpatient database
described above, thromboembolism was the most common
serious complication at 6.6%.18 Numerous cases of clots in
the left and right ventricles have been reported,63–67 and thromboembolic events can sometimes constitute the presenting
symptoms of PPCM.67,68 A study of 33 PPCM cases in Senegal
reported LV thrombus in 30% of the patients.69 In light of this
high risk of thromboembolism, anticoagulation is advisable in
PPCM at least during pregnancy and the first 2 months postpartum. Heparin and unfractionated heparin are safe during
pregnancy, and the former is preferred near term because of
its shorter half-life.
Arrhythmias and Antiarrhythmic Therapies
Data on the prevalence of ventricular arrhythmias in PPCM
are limited. Sudden death is frequently reported as a cause
of mortality, suggesting a high prevalence of arrhythmias.
For example, in a retrospective review of 182 patients in
California, 38% of fatalities were ascribed to sudden death.67
One report of 19 patients in Senegal who underwent 24-hour
Holter monitoring revealed nonsustained ventricular tachycardia in 4 patients.70 Ventricular tachycardia can persist,
requiring ablation.71 A retrospective case-control analysis in
19 women with PPCM who received a permanent implantable cardioverter-defibrillator (ICD) for primary prevention
compared with 60 control women with nonischemic DCM
reported a 37% incidence of appropriate ICD therapy over a
mean 3-year follow-up in the women with PPCM and a strong
trend for higher incidence than in the women with nonischemic DCM.72 A recent single-center study in Germany of 7
women with severely reduced EF (mean, 18%) who received
wearable cardioverter/defibrillator life vests documented 4
events of ventricular fibrillation with successful shock therapy
in 3 of the women over a mean follow-up of 81 days.73 In contrast, however, a larger retrospective registry study of aftermarket wearable cardioverter/defibrillators in 107 women
with PPCM (average EF, 22%) revealed no shocks for ventricular tachycardia or fibrillation over an average follow-up
of 4 months.74 Only 20% of the women went on to receive a
permanent ICD, largely for persistent ventricular dysfunction.
Thus, because of the high rate of recovery in PPCM, early
implantation of permanent ICD should be avoided, and there
is no clear data-driven basis for recommending early use of
a wearable cardioverter/defibrillator. However, it might be
reasonable to consider wearable cardioverter/defibrillators in
patients with EF <30%, who have been shown to be at high
risk of complications, including mortality (see below), as a
bridge to recovery or ICD implantation in patients who fail to
recover on optimal medical therapy.
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Arany and Elkayam Peripartum Cardiomyopathy 1401
Cardiac Assist Devices
inferior and age-adjusted survival is lower, perhaps reflecting younger age and higher allosensitization.83
Patients with PPCM can present with severe depression of
LV function and demonstrate a rapid deterioration. Inotropes,
intra-aortic balloon pumps, LV and biventricular assist
devices, and extracorporeal membrane oxygenation should be
considered in these cases and have been used successfully.75–79
Aggressive treatment should generally be sought in light of
the frequent recovery of patients with PPCM. When recovery
does not occur, cardiac assist devices can serve as a bridge to
transplantation.
Four women (4%) in the IPAC study died. Recent national
inpatient databases reveal in-hospital mortalities of 1.3%,18,32
but they do not include postdischarge information. Longer-term
follow-up in 100 patients in 2 Midwestern academic centers
showed a mortality of 11% over a mean of 8 years. In a statewide North Carolina study, mortality was 16% at 7 years.30
Obstetric Management
Racial and Geographic Differences
Cases of PPCM that occur during late gestation, although less
common than postpartum, require special consideration. As
noted above, certain medications such as angiotensin-converting enzyme inhibitors and excessive volume depletion must be
avoided. No published data exist to guide decisions on timing
and mode of delivery; in particular, no data exist to indicate
that early delivery or elective caesarian delivery can ameliorate PPCM or improve fetal outcomes. Mean birth weight,
size, and Apgar scores are lower in neonates born to women
with PPCM, likely reflecting earlier gestational age at delivery.17 Stillbirths are more common (odds ratio, 3.8; P<0.0001
in a population study of 535 patients32). Decisions on management and timing and mode of delivery should therefore
be made by a team of cardiologists and obstetricians. Early
delivery needs to be weighed against the risks to the newborn
and should generally be reserved for cases of impending peril
to mother or fetus.
Prognosis in the United States is notably worse in blacks.
In a 2013 retrospective analysis of 52 black and 104 white
patients in 2 centers in California and Louisiana, black
patients had 34% lower rates of LV recovery (40% versus
61%; P=0.02) and a higher incidence of mortality or cardiac
transplantation (P=0.03) despite similar EFs (28%) on presentation.29 In the IPAC study, black patients presented with
a lower EF (31% versus 36%; P=0.008), had a lower average EF at the 1-year follow-up (47% versus 56%; P=0003),
and had a lower rate of recovery (defined as EF >50%: 59%
versus 77%; P=0.03). In a North Carolina statewide registry, 7-year mortality was 24% in black patients compared
with 6% in white patients.30 The causes for the differences
in outcome are uncertain and could include genetic differences (perhaps linked to the higher incidence of PPCM in
this population [see above]) and differences in socioeconomic resources, access to health care, delay in diagnosis,
and other environmental variables. Outcome in Hispanic
women, on the other hand, does not appear significantly
worse than in non-Hispanic whites.32
Fewer data exist on prognosis outside the United
States. A prospective PPCM national registry in Germany
that began in 2004 has thus far reported 115 patients. At 6
months, 47% of patients had fully recovered, 2% died, and
15% had major events or persistent cardiomyopathy with EF
<35%.56 In a single-center study of 45 patients with PPCM
in Pakistan, 71% recovered LV function within 6 months,
and no deaths were reported, although 9% of women experienced a thromboembolic stroke.84 In a nationwide study
of 104 PPCM patients in Japan, 4 women died (4%), and
63% of survivors recovered LVEF (>50%) at 6 months.85
These outcomes are similar to contemporary outcomes in
the United States (see above).
On the other hand, a recent single-center study of 30
patients in Cape Town, South Africa, reported 5 deaths (17%)
in a mean follow-up duration of 3.5 years34 (accounting for
the majority of deaths in a larger cohort of 152 patients presenting with cardiovascular disease in pregnancy86). In a
larger study of 176 patients in Soweto, South Africa, 13%
died and 25% had persistent LVEF <35% at 6 months.87 Only
21% of the survivors had fully recovered LVEF (>55%). The
large majority of women in these studies were of African origin, perhaps explaining some of the difference in outcome.
Similarly poor outcomes were reported in a 2-center study
in Istanbul, Turkey, in which 10 of 42 patients (24%) with
PPCM died, and only 30% of the patients had recovered LV
function at 6 months.88 In summary, outcomes remain poor
Prognosis
The prognosis of PPCM in the United States has improved
since its description in 1971. The recently completed prospective Investigations of Pregnancy Associated Cardiomyopathy
(IPAC) study enrolled 100 women from multiple centers
throughout the United States and followed their clinical
course for 12 months with careful clinical evaluations, including repeated echocardiography. This study found that 71% of
the women recovered LVEF to >50%, whereas only 13% had
major events or persistent cardiomyopathy with EF <35%.80
Recovery occurred almost uniformly by 6 months, with little
change in EF thereafter, as has been noted by previous studies.11,81 Recovery of LVEF after 6 months can sometimes
occur, however, and should not be ruled out.
Transplantation
Despite the frequent good outcomes in patients with PPCM,
a significant fraction of patients eventually require transplantation, often with bridging via mechanically assisted
circulatory support. A study of 99 patients with PPCM
who received durable mechanically assisted circulatory
support between 2006 and 2012 reported that outcomes
were generally better than for the 1159 women with nonPPCM cardiomyopathy but 48% went on to receive cardiac
transplantation.82 Only 4 patients had the explant removed
because of recovery. Five percent of cardiac transplantations in women in the United States are performed for an
indication of PPCM.83 Compared with women receiving transplantations for other indications, graft survival is
Mortality
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1402 Circulation April 5, 2016
for women of certain ancestries and in certain geographic
areas, especially Africa.
the presence of preeclampsia with PPCM portends improved
outcome thus remains uncertain.
Predictors of Recovery
Recurrence With Recurrent Pregnancies
In addition to racial background and in part independently
from it, EF at presentation best predicts rate of recovery. In
the IPAC study, only one third of the 27 women with LVEF
<30% at presentation recovered EF to >50% at 1 year. None
of the women who also had evidence of dilation (LV end-diastolic diameter >6.0 cm) recovered compared with recovery in
nearly 90% of the 65 women who presented with LVEF >30%
(P=0.003).80 Events (death, LV assist device, or heart transplantation) occurred almost exclusively in women with LVEF
<30% at presentation compared with those with LVEF ≥30%
(82% versus 99% event-free survival; P=0.004; Figure 3). In
a recent study of 187 patients (mostly from California), mean
EF was 31% in women who recovered EF to >50% at 6 months
versus 23% in women who did not (P<0.0001).89 Similarly, in
the German cohort, mean presenting EF was 28% in women
who improved versus 17% in those who did not (P<0.0001).56
However, it is important to note that reduced EF is not a specific predictor of failure to recover and thus should not be an
indication for premature device implantation or cardiac transplantation.89 Interestingly, LVEF at presentation in the Soweto
study did not predict outcome in this large cohort,87 in contrast to US studies. Lower levels of plasma troponin or brain
natriuretic peptide have also been associated with improved
outcomes.90 However, like LVEF, their predictive accuracy is
not sufficient to affect clinical decisions.
There is ongoing debate on the question of whether the
presence of hypertension or preeclampsia predicts better outcomes. In patients in whom these conditions contribute to the
development of PPCM, resolution of preeclampsia or gestational hypertension may, for example, accelerate resolution.
Consistent with this notion, in the German cohort, 49% of
women who improved had hypertension compared with only
7% of those who did not improve (P=0.009).56 In the Soweto
study, blood pressure had an odds ratio of 0.97 per 1 mm Hg
for poor recovery (P=0.02).87 In the nationwide Japanese
study of 102 women, of whom 41% had hypertension during
pregnancy, the presence of hypertension was independently
associated with shorter hospital stay and moderately improved
EF at the 7-month follow-up (59% versus 51%; P<0.05).85 On
the other hand, preeclampsia or hypertension was not associated with improved outcomes in the IPAC study.80 Whether
The question of the risks of carrying a second pregnancy often
looms large in women who have had PPCM. A recent comprehensive review of the literature on this topic,91 covering
191 recurrent pregnancies, showed that the risk of relapse in
patients with persistent LV dysfunction before their recurrent
pregnancy is much higher than in those who have normalized LV function: 48% of the former group (n=93) had significant deterioration of LV function and 16% died, whereas
27% of the latter group showed deterioration and no deaths
were reported. The risk of worsening PPCM with recurrent
pregnancy is thus substantial. The best predictor for relapse
and deterioration of cardiac function is prepregnancy LVEF,
but normalized LV function does not guarantee an uncomplicated subsequent pregnancy. Demonstration of adequate
cardiac reserve on exercise echocardiography in patients with
recovered LV function has been suggested to confer additional
prognostic value, but this remains uncertain.92 Many women,
however, strongly desire subsequent pregnancies. The decision of whether to proceed is therefore difficult and highly
individual. No firm recommendations on this subject can be
made on the basis of available data. Nevertheless, waiting for
normalization of LV function in the absence of medications is
prudent, and women should be advised that they have a high
risk of recurrence even if their LV function has recovered,
which could lead to a severe and at times persistent decline
in LV function or life-threatening complications, and that
long-term outcomes are currently not known.91 A team-based
approach to decision making, including well-informed clinicians and patients, is highly advocated. If the decision to proceed with pregnancy is made, close monitoring of symptoms,
LV function, and brain natriuretic peptide is highly recommended during and after pregnancy.91
Figure 3. Events in 97 women with peripartum cardiomyopathy (PPCM) in the Investigations of Pregnancy Associated
Cardiomyopathy (IPAC) study. Data from McNamara et al.80
Treatment After Recovery
Because of a lack of long-term follow-up data in women with
PPCM, it is not clear if and when women with the condition
can be considered to have fully recovered. This is an important
issue, bearing on the decision of whether to discontinue longterm medications in young and otherwise healthy women. One
study of 15 patients with full LVEF recovery who stopped taking angiotensin-converting enzyme inhibitors or β-blockers
reported no deterioration of LV function during a 2-year
follow-up.81 Limited cardiac magnetic resonance imaging
data do not detect persistent myocardial damage in women in
PPCM.93 On the other hand, others have reported deterioration
of recovered LV function in a limited number of patients.67
Moreover, an early echocardiographic study of women with
recovered LV function revealed decreased contractile reserve
in response to dobutamine challenge,94 indicating the presence
of persistent subclinical dysfunction. In addition, as discussed
above, women with recovered LVEF remain at high risk of
recurrence with subsequent pregnancies. Together, these data
suggest that cellular and molecular recovery may lag significantly behind echocardiographic recovery. A reasonable
approach to the discontinuation of medications in women
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Arany and Elkayam Peripartum Cardiomyopathy 1403
with complete recovery of LV function would include waiting
until a few months after LV function has recovered, weaning
of medications one at a time, and providing close clinical and
echocardiographic monitoring during the discontinuation process, followed by annual assessment of LV function.
Pathophysiology of PPCM
Hemodynamics and Other Proposed Causes
PPCM has often been ascribed to a failed hemodynamic stress
test during pregnancy. Indeed, pregnancy triggers large hemodynamic shifts that significantly increase cardiac workload
(Figure 2).13 Blood volume and red blood cell mass increase,
leading to increased preload. Cardiac output increases by 20%
to 50%, a consequence of both increased heart rate by ≈15%
to 30% and increased stroke volume by 15% to 25%. Total
vascular resistance decreases by 30%, although afterload
increases again by the end of pregnancy. All of these changes
occur between the first and second trimesters, and patients
with known preexisting structural cardiac disease typically
present with clinical heart failure at this time in pregnancy.95
In striking contrast, PPCM overwhelmingly presents during
the peripartum period (Figure 2). Delivery poses an additional hemodynamic stress, but factors that modify that stress,
including caesarian delivery, do not appear to modify the risk
of developing PPCM. Hemodynamic stresses are thus not
likely to be significant etiologic contributors to PPCM.
Myocarditis has often been put forward as a cause of
PPCM, driven largely by the frequent but variable observation
of inflammatory infiltrates on right-sided heart endomyocardial biopsies.14 However, similar infiltrates are often found in
endomyocardial biopsies from control groups. For example,
in 1 study, 71% of women with PPCM and 73% of matched
control subjects harbored evidence of coxsackie or echovirus infection.96 Similarly, a polymerase chain reaction study
on endomyocardial biopsy specimens from 26 patients with
PPCM revealed a 30.7% prevalence of viral genomes often
implicated in myocarditis, including parvovirus B19, but the
prevalence was identical (30.3%) in a control group.97,98 The
specificity of these findings is thus poor, and the role of myocarditis in PPCM remains uncertain. Right-sided heart biopsies are no longer indicated in the diagnostic workup of PPCM
and are rarely done. Similarly, reports of cardiac magnetic resonance imaging in the acute phase of PPCM in a small number of patients have suggested the presence of inflammation in
some patients,99,100 although a recent evaluation of 40 patients
in the IPAC study showed a pattern suggestive of myocarditis
in only 1 patient (unpublished data, Erik B. Schelbert, MD,
2016). The utility of magnetic resonance imaging in the diagnosis of PPCM is thus uncertain at this time.
A number of other potential causes for PPCM have
also been proposed, with limited supporting data thus far.
Microchimerism, with fetus-derived cells that can persist
in the immune-suppressed pregnant state and may lodge in
the maternal heart, has been proposed as a trigger for autoimmunity after delivery.7 On the other hand, microchimeric
fetal cells that traffic the heart have been proposed to help
injured myocardium and to be beneficial.101 Various forms
of malnutrition have also been proposed, including iron and
selenium deficiencies, and may represent special aggravating circumstances unique to geographical areas. For example,
a recent case-control study of 39 patients in Nigeria, where
the incidence of PPCM is disproportionally high, revealed
mean serum selenium levels that were half that in controls
(P<0.001),26 although this observation is not seen elsewhere
in sub-Saharan Africa.102
In short, until recently, the causes of PPCM have remained
unclear. Recent work, however, has significantly advanced
our understanding of the disease. The results are beginning
to elucidate 2 novel aspects of PPCM: a critical toxic role for
late-gestational hormones on the maternal vasculature and
an increasing understanding of the genetic underpinnings of
PPCM. These recent developments are discussed below
The Vasculo-Hormonal Hypothesis
Prolactin
A landmark 2007 article first introduced the notion that PPCM
is a vascular disease triggered by the hormonal changes of
late pregnancy. Although the idea was proposed in the past,103
experimental support for it was lacking. The authors developed
a mouse model of PPCM in which the STAT3 transcription
factor was genetically deleted specifically in cardiomyocytes.
In support of generating this model, expression of STAT3 was
reduced in the LVs from patients with end-stage heart failure
caused by PPCM compared with nonfailing control subjects.
Loss of STAT3 in murine hearts leads to reduced expression
of genes that protect the heart against reactive oxygen species,
most notably manganese superoxide dismutase (MnSOD),
which neutralizes superoxides generated by the robust mitochondrial activity in beating cardiomyocytes. The consequent
rise in reactive oxygen species leads to the secretion, via a
still unclear mechanism, of cathepsin D. This extracellular
peptidase then cleaves prolactin, a hormone specific to late
pregnancy, into a 16-kDa fragment that promotes apoptosis in
endothelial cells. As a result, STAT3 cardiac knockout mice
reveal significant vascular dropout during late pregnancy
and consequent pregnancy-induced DCM, that is, PPCM
(Figure 4). The most compelling aspect of this study, which
is proof of the key role played by prolactin, came from blocking prolactin secretion from the pituitary with bromocriptine.
Treatment of STAT3 cardiac knockout mice with bromocriptine completely reversed the observed PPCM.
The same group recently probed more deeply into how
the 16-kDa prolactin fragment triggers endothelial and cardiomyocyte damage.44,104 They showed that 16-kDa prolactin
induces endothelial cells to package miR-146a into exosomes,
small lipid-encapsulated particles, which are then secreted and
taken up by cardiomyocytes. The miR-146a internalized into
cardiomyocytes then suppresses the neuregulin/ErbB pathway, thereby promoting cardiomyocyte apoptosis. Strikingly,
circulating levels of miR-146a are dramatically elevated in
women with PPCM. Moreover, the levels drop significantly
with bromocriptine treatment, demonstrating that prolactin
drives miR-146a secretion. As outlined above, miR-146a may
thus be useful as a biomarker of PPCM. In addition, miR-146a
may become a viable therapeutic target because microRNAs
can be efficiently and specifically inhibited clinically. Indeed,
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1404 Circulation April 5, 2016
Figure 4. Vasculo-hormonal hypothesis of the
pathophysiology of peripartum cardiomyopathy
(PPCM). See text for details.
treatment of the STAT3 model of PPCM with locked nucleic
acid (LNA)–modified antisense oligonucleotides to silence
miR-146a partially rescued cardiac capillary density and contractile function. Moreover, LNA–miR-146a did not inhibit
lactation because the linolenic acid acts downstream of the
16-kDa prolactin action. Thus, unlike with bromocriptine,
therapy with LNA-miR-146a would allow continued nursing
of the newborn.
These data thus convincingly showed that, at least in this
murine model, a peripartum hormone (prolactin) plus a cardiac
predisposition (in this case, absence of STAT3 in the heart)
conspire to trigger vasculopathy and consequently PPCM.
Soluble Fms-Like Tyrosine Kinase 1
A very similar vasculo-hormonal paradigm was recently recapitulated in a different mouse model of PPCM in which there
is cardiac-specific deletion of proliferator-activated receptorgamma coactivator-1α (PGC-1α), a powerful transcriptional
regulator.105 Like STAT3, PGC-1α drives the expression of
MnSOD, thus suppressing reactive oxygen species. In addition, PCG-1α drives the expression of vascular endothelial
growth factor (VEGF), the most widely studied angiogenic
factor.106 Cardiac deletion of PGC-1α thus promotes vasculotoxicity by 2 pathways: the activation of an antivascular 16-kDa prolactin-mediated pathway (as in the STAT3
model) and the loss of a provascular VEGF-mediated pathway
(Figure 4). Accordingly, only the combination of bromocriptine and VEGF therapies rescues PPCM in these animals.
The observations above raised the question of what hormone during pregnancy is inhibiting the VEGF pathway and
triggering PPCM in the PGC-1 model. During late gestation
in placental mammals, the placenta secretes into the maternal
circulation numerous hormones, including a soluble variant
of the VEGF receptor 1, soluble Fms-like tyrosine kinase 1
(sFlt1). Most free VEGF in the maternal circulation is neutralized by sFlt1 during late gestation.107 The heart and other
organs defend themselves from this insult in part by local
secretion of VEGF, but this is diminished and insufficient in
the PGC-1α model of PPCM. Administering sFlt1 to nulliparous PGC-1α animals was sufficient to cause cardiomyopathy,
even in the absence of pregnancy, demonstrating that sFlt1 is
a key component of the gravid state that triggers PPCM in
these animals. Thus, sFlt1 and prolactin are 2 potentially vasculotoxic hormones of late gestation that can trigger PPCM in
sensitized hosts.
The placental secretion of sFlt1 is markedly elevated in
preeclampsia107 and twin gestations.108 The maternal heart is
thus exposed to significantly higher levels of sFlt1 in these
conditions, likely explaining the strong epidemiological link
between preeclampsia, twin gestations, and PPCM (discussed
above). In fact, women with preeclampsia but without PPCM
still have demonstrable subclinical cardiac dysfunction on
echocardiography,35–37,105 and in a small study (n=20), the
extent of dysfunction correlated well with circulating levels of
sFlt1.105 Levels of sFlt1 are elevated in a subset of women with
PPCM,105 and in the IPAC study, levels of sFlt1 correlated
with clinical heart failure and adverse outcome.108a A small,
nonrandomized, open pilot study (n=11) of extracorporeal
removal of sFlt1 in early preterm preeclampsia showed promising results,109 and a single case study of plasma exchange in
a woman with aggressive PPCM showed accelerated recovery
of heart function.110
Together, these observations indicate that sFlt1, secreted
from the placenta in late gestation, provides a toxic challenge
to the heart and that, in the absence of appropriate defenses,
PPCM can ensue. Together with the STAT3 model, the findings strongly support the notion that PPCM is a vascular
disease, triggered by the hormonal milieu of the peripartum
(Figure 4). This notion has a number of attractive explanatory
attributes. First, it could explain why PPCM typically presents
in the peripartum period, when hormonal changes are greatest,
rather than much earlier in pregnancy, when hemodynamic
changes are greatest (Figure 2). Second, the role of sFlt1
could explain the well-established epidemiological observations that PPCM is strongly associated with preeclampsia and
with multiple gestations, both of which are marked by high
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Arany and Elkayam Peripartum Cardiomyopathy 1405
secretion of sFlt1. Third, the removal of the toxic hormonal
milieu after delivery could explain the frequently found rapid
recovery of ventricular function in PPCM, not typically seen
in other causes of DCM. The hormonal hypothesis also presents clinical diagnostic, prognostic, and therapeutic opportunities. sFlt1, miR-146a, or as-yet-undiscovered hormonal
contributors could become useful biomarkers. Inhibition of
prolactin (eg, with bromocriptine61) or of miR-146a (eg, with
antagomirs), proangiogenic therapy (eg, with VEGF analogs),
or removal of toxic hormones (eg, with apheresis109) could
prove beneficial (Figure 4). These ideas, however, are still
experimental at this stage.
Genetics
An enduring question in the pathogenesis of PPCM is what
rare event predisposes to the disease. One possibility is genetic
background. Arguing against this notion, PPCM is typically
not a familial disease, and pedigrees of patients with PPCM
have not been reported. Moreover, PPCM often does not recur
with a second pregnancy, indicating that any genetic origin, if
existing, is incompletely penetrant. A recent small echocardiographic study of sisters of women with PPCM (n=17) revealed
no obvious cardiac abnormalities.111 However, some evidence
has supported the notion that PPCM may have a hereditary
or genetic component. A genome-wide association study in
79 patients identified a single-nucleotide polymorphism near
the PTHLH gene as being associated with PPCM,112 and
interestingly, PTHLH may regulate vascular homeostasis.113
Familial clustering of PPCM has been noted,114–117 and 15%
of patients in a German cohort had a family history of cardiomyopathy (loosely defined as PPCM, idiopathic cardiomyopathy [DCM], sudden death, or arrhythmias in first-degree
relatives).56 Two groups recently evaluated rare pedigrees of
patients affected by both PPCM and DCM and identified variants in genes encoding myofibrillar proteins, including TTN,
the gene encoding the sarcomere protein titin.118,119 Whether
similar variants would be found in common, sporadic PPCM
remains uncertain.
Most recently, a genetic study was undertaken with 172
patients with PPCM who were not preselected for family history or other indexes of genetic origin.120 Targeted sequencing
of 43 genes known to associate with DCM revealed a striking 15% prevalence in the patients with PPCM of high-impact
nonsense, frameshift, and splicing variants (P=1.3×10−7 compared with the control group). Interestingly, the prevalence
was similar to that found in a large cohort of DCM cases
(17%; P=0.81). Strikingly, two thirds of identified truncating
variants were in TTN (prevalence of 10%; P=2.7×10−10 versus 1.4% in reference population). Equally strikingly, 14 of
these 17 TTN truncating variants were located in the A band of
titin (P=0.0018 versus the reference population; Figure 5).120
Variants in subjects with DCM show a similar predilection for
affecting the A band.121,122
These surprising findings indicate that PPCM often has
a genetic cause and that PPCM shares a genetic origin with
familial and sporadic DCM. Post hoc subgroup analyses
also revealed interesting observations: (1) TTN variants were
identified in both black and white women; (2) in the subset
of women enrolled in the clinically well-characterized IPAC
cohort (n=83), the presence of TTN variants correlated with
lower EF at the 1-year follow-up (P=0.005); and (3) the burden
of truncating TTN variants in subjects without hypertension
was nearly 10-fold higher than in subjects with hypertension
(23% versus 2.5%; P=0.005). These post hoc findings need
further validation before clinical recommendations can be
made.
These genetic findings raise a number of questions. PPCM
and DCM are not clinically identical. For example, patients
with DCM recover LV function much less frequently than
patients with PPCM, and DCM rarely occurs in young women.
It thus remains enigmatic what genetic or environmental variables differentiate women who carry TTN truncating variants
and develop PPCM from those women who develop DCM or
from those who develop neither. It will also be of interest to
elucidate the mechanistic interaction between truncations in
TTN and late gestational antivascular insults.
Figure 5. Sites within the TTN gene of truncating variants identified in women with peripartum cardiomyopathy (PPCM) and comparison
with variants found in patients with dilated cardiomyopathy (DCM) and healthy control subjects. Top, Schematic of a sarcomere spanned
by titin. Bottom, Schematic of the TTN open reading frame. Red indicates the Z band; blue, the I band; green, the A band; and purple,
the M band. Reprinted with permission from Ware et al.120 Copyright © 2016, Massachusetts Medical Society.
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1406 Circulation April 5, 2016
Conclusions
Tremendous progress has been made in the last few years in
our understanding of PPCM, both clinically and mechanistically. However, this exciting progress has not yet translated
into tangible benefits for patients. No proven disease-specific
efficacious therapies exist yet, and specific diagnostic or prognostic tests are lacking. Management of PPCM remains largely
limited to the appropriate use of routine neurohormonal antagonists used in other forms of DCM. A number of developments
would significantly aid the progress in understanding PPCM.
First, in light of the relatively rare nature of PPCM, multicenter
collaborations and registries are urgently needed. A worldwide prospective registry that began in 2012 is aiming at 1000
patients and has thus far reported 100 patients, half from Africa
and only a handful from the United States.123 Second, further
research support is needed. Currently, the National Institutes of
Health does not support a single project that studies PPCM.124
Third, organized patient advocacy groups would help both galvanize support and recruit subjects for research; no such group
currently exists. Advancement in the understanding of PPCM
is at an inflection point. With appropriate coordinated efforts,
progress in the next few years will be exponential, and translation to the clinic could become a reality.
Disclosures
None.
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Peripartum Cardiomyopathy
Zolt Arany and Uri Elkayam
Circulation. 2016;133:1397-1409
doi: 10.1161/CIRCULATIONAHA.115.020491
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